CN106478654A - The pharmaceutical composition of lomustine and its application in biological medicine - Google Patents
The pharmaceutical composition of lomustine and its application in biological medicine Download PDFInfo
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- CN106478654A CN106478654A CN201610818167.8A CN201610818167A CN106478654A CN 106478654 A CN106478654 A CN 106478654A CN 201610818167 A CN201610818167 A CN 201610818167A CN 106478654 A CN106478654 A CN 106478654A
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- compound
- lomustine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
- A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses the pharmaceutical composition of lomustine and its application in biological medicine, containing the natural products compound (I) that lomustine and a kind of structure are novel in the pharmaceutical composition of the lomustine that the present invention is provided, when lomustine, compound (I) independent role, there is therapeutic action to epilepsy；When lomustine and compound (I) synergy, the therapeutic effect to epilepsy is improved further, can develop into the medicine for the treatment of epilepsy, has prominent substantive distinguishing features and significant progress compared with prior art.
Description
Technical field
The invention belongs to biomedicine field, is related to the new application of lomustine, and in particular to the medicine group of lomustine
Compound and its application in biological medicine.
Background technology
Lomustine is CCNS medicine, and to being in G1-S border, or the cell of S early stage is most sensitive, to G2
Also there is inhibitory action phase.After this product enters human body, its molecule is fractured into two parts from carbamyl amine key：One is chloroethene amine portion
Point, by chlorinolysis from, form ethene carbonium ion, play hydrocarbonylation effect, cause DNA to rupture, RNA and protein receptor to hydrocarbonylation,
These are mainly relevant with Synergistic action.
Content of the invention
It is an object of the invention to provide a kind of pharmaceutical composition of lomustine, contains Luo Mosi in the pharmaceutical composition
The novel natural products of spit of fland and a kind of structure, lomustine and the natural products can be with Synergistic treatment epilepsies.
The above-mentioned purpose of the present invention is achieved by techniques below scheme：
A kind of compound (I) with following structural formula,
A kind of pharmaceutical composition of lomustine, including lomustine, compound as claimed in claim 1 (I) and medicine
Acceptable carrier on, is prepared into the formulation of needs.
Further, pharmaceutically acceptable carrier include diluent, excipient, filler, adhesive, wetting agent,
Disintegrant, sorbefacient, surfactant, absorption carrier or lubricant.
Further, the formulation include tablet, capsule, oral liquid, mouth containing agent, granule, electuary, pill, powder,
Paste, sublimed preparation, supensoid agent, pulvis, solution, injection, suppository, spray, drops or patch.
The preparation method of above-claimed cpd (I), comprising following operating procedure：A giant knotweed is crushed by (), with 60～70% ethanol
Circumfluence distillation, merges extract, is concentrated into nothing alcohol taste, uses petroleum ether, ethyl acetate and water saturated extracting n-butyl alcohol successively,
Respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B in () step (a), n-butyl alcohol extract is used
Macroreticular resin removal of impurities, first with 10% ethanol elution, 12 column volumes, then with 70% ethanol elution, 15 column volumes, collects 70% and washes
De- liquid, reduced pressure concentration obtain 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution concentrate is divided with purification on normal-phase silica gel
From it is 50 to use volume ratio successively:1、25:1、15:1 and 5:1 methylene chloride-methanol gradient elution obtains 4 components；(d) step
Suddenly in (c), component 4 is separated further with purification on normal-phase silica gel, and it is 10 to use volume ratio successively:1、5:1 and 2:1 methylene chloride-methanol ladder
Degree affords 3 components；E component 2 is bonded with octadecylsilane in () step (d) reverse phase silica gel is separated, with volume hundred
Point concentration is 70% methanol aqueous solution isocratic elution, collects 7～13 column volume eluents, being concentrated under reduced pressure to give of eluent
Compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 65% alcohol heat reflux, is merged and is extracted
Liquid.
Further, in the preparation method of compound (I), the macroreticular resin is AB-8 type macroporous absorbent resin.
Further, in the preparation method of compound (I), in step (a), ethyl acetate is replaced to be extracted with dichloromethane
Take, obtain dichloromethane extract.
Application of the above-claimed cpd (I) in the medicine for preparing treatment epilepsy.
Application of the pharmaceutical composition of above-mentioned lomustine in the medicine for preparing treatment epilepsy.
Advantages of the present invention：
Containing the natural product that lomustine and a kind of structure are novel in the pharmaceutical composition of the lomustine that the present invention is provided
Thing, when lomustine, compound (I) independent role, has therapeutic action to epilepsy；Lomustine and compound (I) joint are made
Used time, the therapeutic effect to epilepsy improve further, can develop into the medicine for the treatment of epilepsy.
Specific embodiment
The essentiality content of the present invention is further illustrated with reference to embodiment, but the present invention is not limited with this and protected model
Enclose.
Embodiment 1：Compound (I) is separated and is prepared and structural identification
Separation method：A giant knotweed (2kg) is crushed by (), extract (20L × 3 time) with 65% alcohol heat reflux, is merged and is extracted
Liquid, is concentrated into nothing alcohol taste (4L), uses petroleum ether (4L × 3 time), ethyl acetate (4L × 3 time) and water saturated n-butanol successively
(4L × 3 time) extract, and respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；In (b) step (a)
N-butyl alcohol extract AB-8 type macroreticular resin removal of impurities, first with 10% ethanol elution, 12 column volumes, then uses 70% ethanol elution
15 column volumes, collect 70% eluent, and reduced pressure concentration obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol is washed
De- concentrate is separated with purification on normal-phase silica gel, and it is 50 to use volume ratio successively:1 (8 column volumes), 25:1 (8 column volumes), 15:1 (8
Column volume) and 5:The methylene chloride-methanol gradient elution of 1 (10 column volumes) obtains 4 components；Component 4 in (d) step (c)
Separated with purification on normal-phase silica gel further, it is 10 to use volume ratio successively:1 (8 column volumes), 5:1 (10 column volumes) and 2:1 (5 posts
Volume) methylene chloride-methanol gradient elution obtain 3 components；E in () step (d), component 2 is bonded with octadecylsilane
Reverse phase silica gel is separated, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 70%, collects 7～13 column volume wash-outs
Liquid, eluent are concentrated under reduced pressure to give compound (I) (purity is more than 98%).
Structural identification：HR-ESI-MS shows [M+H]+For m/z 219.1161, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C15H22O, degree of unsaturation are 5.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz)：H-1 β (1.78, m), H-2 α
(2.23, m), H-2 β (1.76, m), H-3 (5.54, J=7.8,4.8Hz), H-5 (2.67, dd, J=11.4,7.8Hz), H-6 α
(2.09, m), H-6 β (1.68, m), H-8 α (1.37, m), H-8 β (1.56, m), H-9 α (1.74, m), H-9 β (1.71, m), H-
12 (1.72, s), H-13a (4.45, s), H-13b (4.76, s), H-14 (1.37, s), H-15 (1.84, s)；Carbon-13 nmr spectra
Data δC(ppm, CDCl3, 125MHz)：47.5 (CH, 1-C), 32.1 (CH2, 2-C), 121.2 (CH, 3-C), 134.1 (C, 4-
C), 51.2 (CH, 5-C), 25.3 (CH2, 6-C), 90.2 (C, 7-C), 34.3 (CH2, 8-C), 39.5 (CH2, 9-C), 85.7 (C,
10-C), 145.4 (C, 11-C), 30.8 (CH3, 12-C), 112.2 (CH2, 13-C), 24.6 (CH3, 14-C), 33.3 (CH3, 15-
C).Show that the compound has three unimodal methyl signals (δ in the hydrogen spectrum of compoundH1.72,1.37 and 1.84), an end is double
Key proton signal [δH4.45 (1H, s) He 4.76 (1H, s)], and an olefinic methine proton signal [δH5.54 (1H, J=
7.8,4.8Hz)].The carbon spectrum of the compound shows 15 carbon signals, wherein has two groups of double bond carbon signals, and two company's oxygen carbon
Signal.Comprehensive high resolution mass spectrum and nuclear magnetic data, the compound may be a sesquiterpenoids.Consulting literatures are permissible
Find out the compound and 7 α of known compound, 10 α-Epoxyguaiane-4 α, 11-diol have similar structure.Both relatively
Nuclear-magnetism and high-resolution number it has been found that maximum compared to 7 α, 10 α-Epoxyguaiane-4 α, 11-diol in noval chemical compound
Difference is to have had more i.e. two double bonds of two degrees of unsaturation.In the HMBC spectrum of noval chemical compound, H-15/C-3, H-15/C-4, H-
Correlation explanation C-3 and C-4 position between 3/C-4 is double bond.Meanwhile, H-12/C-7, H-12/C-13, H-13/C-7, H-13/
Correlation between C-11 illustrates that another terminal double bond present in the compound is located at C-11 and C-13 position.Therefore, the change
Compound remains the guainane type sequiterpene that C-10, C-7 position forms oxygen bridge.In ROESY spectrum, H-5 and H-1, H-14/H-
Coherent signal between 1, H-14/H-8 β may infer that the compound H-1, H-5 and H-14 be all positioned at β position.Comprehensive hydrogen spectrum,
Carbon spectrum, HMBC spectrum and ROESY spectrum, and document is with regard to correlation type nuclear magnetic data, can determine substantially that the compound is as follows,
By ECD test, spatial configuration determines that theoretical value is basically identical with experiment value further.
The compound chemical formula and carbon atoms numbered as follows：
Embodiment 2：Pharmacological action
The present embodiment makes epilepsy model with 6,000,000 U/kg of rats by intraperitoneal injection penicillin, observes drug therapy epilepsy
Effect.
1st, materials and methods
1.1 animal
Wistar rat 90, male and female half and half, 120 ± 20g of body weight, carried by Heilongjiang University of Chinese Medicine's Experimental Animal Center
For.
1.2 reagents and sample
Lomustine is purchased from Nat'l Pharmaceutical ＆ Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.Benzene
Appropriate English sodium：Tianjin power life pharmacy head factory production；Penicillin：Harbin Pharmaceutical General Factory；Urethane：Harbin Pharmaceutical General Factory.
1.3 instrument
Two road physiograph of LMB-2B type：Chengdu Instruement Factory produces.
Prepared by 1.4 animal packets and model
Take rat 50, male and female half and half, 5 groups are randomly divided into, per group 10, respectively：Model control group, positive controls
(dilantin sodium 4.2mg kg-1), lomustine group (80mg kg-1), compound (I) group (80mg kg-1), lomustine with
Compound (I) composition group【40mg·kg-1Lomustine+40mg kg-1Compound (I)】.Each group administration group is according to respective agent
Amount administration, is oral administration gavage administration.Model group gavages consubstantiality ponding.Each group animal all administration or distilled water 1h after, abdominal cavity
Injection 6,000,000 U/kg of penicillin, observes rat behavior.
1.5 epileptic rat convulsions latencies are tested
After lumbar injection penicillin, the incubation period of each group mouse epilepsy outbreak behavior and epilepsy outbreak is observed.
1.6 seizures in rats degree observation experiments
Epilepsy outbreak behavior observation, with reference to Racine standard：0 grade：Reactionless or stopping of twitching.I grade：Rhythmicity mouth or face
Portion twitches.II grade：Nod or whipping.III grade：Single limb is twitched.IV grade：Many limbs are twitched or tetanic.V grade：Comprehensive tonic-clonic
Outbreak.
1.7 statistical method
Experimental data mean ± standard deviationRepresent, application SPSS18.0 version statistical software carries out single factor test variance
Analysis and t inspection, statistically significant as difference with P ＜ 0.05.
2nd, experimental result
2.1 on the preclinical impact of penicillin induction epileptic rat convulsions
Compare with model control group, positive controls rat convulsions incubation period significantly extends (P ＜ 0.01)；With model comparison
Group is compared, and lomustine significantly extends (P ＜ 0.01) with compound (I) composition group rat convulsions incubation period；With model comparison
Group compares, lomustine group, compound (I) group rat convulsions prolongation of latency (P ＜ 0.05).The results are shown in Table 1.
The impact of 2.2 pairs of penicillin induced rat epilepsy outbreak degree
Compare with model control group, positive controls seizures in rats degree is substantially reduced (P ＜ 0.01)；With model pair
Compare according to group, lomustine is substantially reduced (P ＜ 0.01) with compound (I) composition group seizures in rats degree；With model
Control group compares, and lomustine group, compound (I) group seizures in rats degree reduce (P ＜ 0.05).It is shown in Table 2.
Table 1 is on the preclinical impact of penicillin induction epileptic rat convulsions
| Group | Incubation period (s) | Convulsions percentage (%) |
| Model control group | 45.4±16.9 | 100% |
| Positive controls | 87.5±17.3 | 70% |
| Lomustine group | 73.3±18.3 | 80% |
| Compound (I) group | 72.7±18.6 | 80% |
| Lomustine and compound (I) composition group | 85.2±18.8 | 70% |
Impact of the table 2 to penicillin induced rat epilepsy outbreak degree
Penicillin is classical cause epilepsy agent, its acute or light animal epileptic model obtained generally acknowledged.Penicillin can suppress
GABA serotonergic neuron, causes inhibitory synapse activity to weaken or excitatory synapse activity strengthens, so as to cause neuronal excitability
Increase.Paroxysmal depolarising drift can be produced when neuronal excitability postsynaptic potential (EPSP) comprehensively exceedes certain threshold value
(PDS).
As a result show, when lomustine, compound (I) independent role, there is therapeutic action to epilepsy；Lomustine and change
During compound (I) synergy, the therapeutic effect to epilepsy is improved further, can develop into the medicine for the treatment of epilepsy.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit the protection of the present invention with this
Scope.It will be understood by those within the art that, technical scheme can be modified or equivalent,
Essence and protection domain without deviating from technical solution of the present invention.
Claims (10)
1. a kind of compound (I) with following structural formula,
2. a kind of pharmaceutical composition of lomustine, it is characterised in that：Including lomustine, chemical combination as claimed in claim 1
Thing (I) and pharmaceutically acceptable carrier, are prepared into the formulation of needs.
3. the pharmaceutical composition of lomustine according to claim 2, it is characterised in that：Pharmaceutically acceptable carrier
Including diluent, excipient, filler, adhesive, wetting agent, disintegrant, sorbefacient, surfactant, absorption carrier
Or lubricant.
4. the pharmaceutical composition of lomustine according to claim 2, it is characterised in that：The formulation includes tablet, glue
Wafer, oral liquid, mouth containing agent, granule, electuary, pill, powder, paste, sublimed preparation, supensoid agent, pulvis, solution, injection,
Suppository, spray, drops or patch.
5. the preparation method of compound (I) described in claim 1, it is characterised in that comprising following operating procedure：A () is by tiger
Cane is crushed, and is extracted with 60～70% alcohol heat reflux, merges extract, is concentrated into nothing alcohol taste, is used petroleum ether, ethyl acetate successively
With water saturated extracting n-butyl alcohol, petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract is respectively obtained；(b) step
Suddenly n-butyl alcohol extract macroreticular resin removal of impurities in (a), first with 10% ethanol elution, 12 column volumes, then uses 70% ethanol elution
15 column volumes, collect 70% eluent, and reduced pressure concentration obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol is washed
De- concentrate is separated with purification on normal-phase silica gel, and it is 50 to use volume ratio successively:1、25:1、15:1 and 5:1 methylene chloride-methanol gradient is washed
Take off and obtain 4 components；D in () step (c), component 4 is separated further with purification on normal-phase silica gel, it is 10 to use volume ratio successively:1、5:1 He
2:1 methylene chloride-methanol gradient elution obtains 3 components；What e in () step (d), component 2 was bonded with octadecylsilane is anti-
Phase silica gel is separated, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 70%, collects 7～13 column volume eluents,
Eluent is concentrated under reduced pressure to give compound (I).
6. preparation method according to claim 5 to compound (I), it is characterised in that：Step (a) is returned with 65% ethanol heat
Stream is extracted, and merges extract.
7. preparation method according to claim 5 to compound (I), it is characterised in that：The macroreticular resin is AB-8 type
Macroporous absorbent resin.
8. preparation method according to claim 5 to compound (I), it is characterised in that：Dichloromethane generation is used in step (a)
Extracted for ethyl acetate, obtained dichloromethane extract.
9. application of the compound (I) described in claim 1 in the medicine for preparing treatment epilepsy.
10. the pharmaceutical composition of the arbitrary described lomustine of claim 2～4 prepare treatment epilepsy medicine in should
With.
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| CN201610818167.8A CN106478654A (en) | 2016-09-12 | 2016-09-12 | The pharmaceutical composition of lomustine and its application in biological medicine |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105777685A (en) * | 2016-04-28 | 2016-07-20 | 周俭 | Pharmaceutical composition of felodipine and pharmaceutical application of pharmaceutical composition |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105777685A (en) * | 2016-04-28 | 2016-07-20 | 周俭 | Pharmaceutical composition of felodipine and pharmaceutical application of pharmaceutical composition |
Non-Patent Citations (1)
| Title |
|---|
| JIE-QING LIU，等: "Cytotoxicity of naturally occurring rhamnofolane diterpenes from Jatropha curcas", 《PHYTOCHEMISTRY》 * |
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